Systemic lupus erythematosus (SLE) is a complex autoimmune disorder initiated by a loss of immunologic tolerance to self-antigens. Our previous studies in mouse demonstrated that members of the SLAM gene cluster are responsible for the elevated ANA titers and predisposition to SLE seen in the B6.S/e)bcongenic strain which carries the NZM-derived lupus susceptibility loci, Slelb. Slelb is the most potent member of the NZM2410-derived Sie1 multi-gene locus and has been shown to play a role in the first step toward the development of fatal lupus nephritis, causing elevated ANA titers as well as the B cell abnormalities seen in the NZM2410 mouse strain. In addition, the chromosomal interval in the mouse that contains these genes is syntenic to human chromosome 1q21-q23 and multiple human linkage studies have associated this region with susceptibility to lupus. Furthermore, it has been shown that genes in the SLAM family play important roles in regulating immune responses, encoding adhesion molecules that mediate co-stimulatory and/or inhibitory signaling during cell-cell interactions between T cell, B cell, monocyte and NK cell lineages. Hence, the current proposal will test the hypothesis that allelic variants of the SLAM gene cluster confer susceptibility to lupus in humans. Variants within these genes have been identified using information from publicly available databases and examined for their frequency in a large cohort consisting of 4320 SLE cases and unrelated controls. Functional analyses of the mutations identified in this screen will be used to prove our hypothesis. The identification of disease-associated sequence polymorphisms represents a major advance in understanding lupus pathogenesis. Knowledge gained from these studies is critical to identifying those individuals at greatest risk for lupus as well as to the development of new, early-treatment therapeutic strategies. Relevance to Public Heath: Members of the SLAM gene cluster have been shown to be important in maintaining proper function of the immune system. Mutations in the SLAM gene cluster shown to be responsible for proper expression and function of these genes in lupus patients will have far-reaching implications, perhaps predisposing individuals to a variety of systemic autoimmune diseases. Our long term goal is to develop a screen for these functional variants in order to identify individuals at greatest risk prior to the onset of clinical disease and major organ damage and to identify novel therapeutic targets.